Date Published: September 4, 2007
Publisher: Public Library of Science
Author(s): Shahram Aarabi, Michael T Longaker, Geoffrey C Gurtner
Abstract: The authors examine the process of hypertrophic scar formation, the results of current treatments, and areas of research likely to lead to significant advances in the field.
Partial Text: Hypertrophic scar formation is a major clinical problem in the developing and industrialized injuries, and surgical procedures can give rise to exuberant scarring that resaults in permanent functional loss and the stigma of disfigurement. Figure 1 illustrates the scope of the problem. Annually, over 1 million people require treatment for burns in the United States , 2 million are injured in motor vehicle accidents , and over 34 million related surgical procedures are performed . Although the incidence of hypertrophic scarring following these types of injuries is not known, it is a common outcome that creates a problem of enormous magnitude. Treatment of these cases is estimated to cost at least $4 billion per annum in the US alone . The incidence of burns and traumatic injuries is even greater in the developing world . This review will examine the process of hypertrophic scar formation, the results of current treatments, and areas likely to lead to significant advances in the field.
Advances over the past 60 years have allowed us to extend the lives of patients whose injuries would previously have been invariably fatal. Fire disasters such as those at the Rialto concert hall (1930)  and the Cocoanut Grove nightclub (1942)  led to the development of new treatments, such as fluid resuscitation, to prevent death in the early stages following burn injury. World War II led to the development of critical care medicine , further improving the ability to keep those with traumatic injuries alive until surgical management of their wounds was possible. Antibiotics and aggressive surgical debridement have also contributed to the survival of the great majority of burn and trauma patients. However, despite advances in life-saving technology, progress to prevent the late functional and aesthetic sequelae of hypertrophic scar formation has been slow .
Clinical experience suggests that hypertrophic scarring is an aberrant form of the normal processes of wound healing . However, the etiology of the overexuberant fibrosis is unknown. Hypertrophic scarring should be distinguished from keloid formation, the other major form of excessive scarring seen in humans. There is stronger evidence for genetic predisposition in keloid formation than in hypertrophic scarring, although both occur more frequently in certain groups (e.g., people of African and Asian descent). Keloids are characterized by overgrowth of fibrosis beyond the boundaries of the original injury, while hypertrophic scars do not extend beyond the original wound margins. Keloids and hypertrophic scars can also be differentiated by established histopathological criteria, which include differences in collagen density and orientation, vascularity, and other factors [17,18].
The inflammatory response is a normal component of the wound healing process, serving both as an immunological barrier from infection and as a stimulus for fibrosis to close the site of injury. Observations from human pathological specimens and from healing fetal wounds suggest that a robust inflammatory response may underlie the excessive fibrosis seen in hypertrophic scar formation [16,18]. Mast cells, macrophages, and lymphocytes have all been implicated in this process [16,18]. For example, mast cells have been shown to directly regulate stromal cell activity in vitro  as well as to be strongly associated with the induction of fibrosis in vivo . Mechanical activity, age-specific changes, and delayed epithelialization have all been implicated as inciting factors for this intense inflammatory response.
Epithelial cells have important roles in normal skin physiology, which include acting as stem cell niches and participating in complex signaling pathways to regulate mesenchymal cell function. The net results of these functions are the constant renewal of skin layers and the regulation of matrix deposition and remodeling. Cell-based skin substitutes take advantage of the regenerative nature of skin and are clinically used to cover wounds, but their utility in subsequent scar formation remains unknown. Epidermal stem cells are thought to act in concert with mesenchymal cells in the dermal papillae, functioning to recruit new cells to sites of skin regeneration [43,44]. However, large traumatic skin defects (such as those following burn injuries) destroy the resident epidermal stem cell population and cannot be spontaneously regenerated.
Following injury, the wound is a complex and mechanically unique environment [57,58] with multiple levels of interaction between cells and the surrounding milieu. Fibroblasts and keratinocytes respond to the density and orientation of collagen and other matrix components [59–61]. As a result, cells near the wound margin proliferate while those further away from the edge of the wound are less active [62,63]. At the same time, these cells are actively producing and remodeling the surrounding matrix. It is this delicate balance that is responsible for a rapid and healthy response to injury and, when disturbed, leads to aberrant wound healing.
The complex interplay between cell influx into the wound bed, environmental factors in the surrounding skin, and various cytokine mediators makes the task of manipulating the wound environment to promote regeneration appear daunting. Presently, most therapies consist of a single cell type or cytokine being added to the healing wound in the hopes that this will result in perfect healing. As we have described, monotherapy is unlikely to be effective. However, it is equally improbable that the entire web of factors that promote tissue regeneration can be incorporated into a single therapeutic strategy. It is likely that the development of more effective therapeutics will require an incorporation of known environmental factors along with cellular components to promote healing. A comprehensive strategy taking into account both the cellular (seed) and environmental (soil) contributions to hypertrophic scar formation will have the highest likelihood of therapeutic success against this currently incurable condition.